Expert Analysis

The European Society of Cardiology (ESC) Congress 2017 presented an impressive number of trials potentially impacting interventional cardiology. The following are comments about several of the trials and links to the respective trial summaries and slides if available. What is unique about this format is the opportunity not only to review the trial data but also to have an expert perspective on the significance and potential impact of the trial to current or in some cases future clinical practice. Thanks to the excellent and dedicated work of the contributors.

The VIVA trial is an impressive experience based on the number of screenings performed; 50,168 men between 65 and 74 years of age were invited to participate. Screening focused on ultrasound imaging for abdominal aortic aneurysm (AAA) and Doppler ankle-brachial index diagnosis of peripheral arterial disease (PAD) along with blood pressure (BP) measurement for hypertension. Ultimately, the study showed a 7% absolute decline in mortality for the screened/intervention group predominantly based on effective management of AAA. By 2014 cost estimates, the study demonstrated a cost efficiency based on a yearly accepted cost of $40,000 per life year saved.

Although the results are impressive, it seems much opportunity was lost based on the usual realities of patient management and, in this case, focus on AAA treatment. Only 75% of men who were offered screening participated, meaning a lost opportunity for 25% of the population. Furthermore, despite adding appropriate antiplatelet and cholesterol-lowering medications and referring hypertensive patients to their primary practitioners, there appears to be no persistent improvement in medical control of risk factors after 6 months based on prescription treatment. Likewise, lifestyle intervention was low, with only a third of AAA- or PAD-screened patients opting to enroll in smoking cessation.

It appears that despite a noble goal, a huge screening effort, and a benefit (mostly from effective management of AAA), it seems to me that so much more might have been achieved by a more aggressive lifestyle intervention and/or risk-related medication treatment potentially providing larger benefit than seen in this study.

The CHANGE DAPT study was a single center, observational study comparing the outcomes of clopidogrel and ticagrelor in over 2,000 patients with acute coronary syndromes (ACS) treated with percutaneous coronary intervention (PCI) and newer-generation drug-eluting stents (DES). In contrast to the landmark randomized PLATO (A Comparison of Ticagrelor and Clopidogrel in Patients With Acute Coronary Syndrome) trial, the CHANGE DAPT study reported a higher rate of composite adverse clinical events in patients with ACS treated with ticagrelor compared with patients treated with clopidogrel. The worse outcome seen with ticagrelor was primarily driven by a more than twofold increased risk of major bleeding.

Are the findings of the CHANGE DAPT study compelling enough to move the needle and change treatment strategy or clinical guidelines for ACS? In a word: No. The treatment groups in this study were not randomized or even contemporaneous. Although intriguing, the results of the CHANGE DAPT study do not diminish the robust benefits in ischemic events including mortality observed in the 18,000+ patient PLATO trial and the 45,000+ patient SWEDEHEART (Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies) registry. The CHANGE DAPT study can be considered hypothesis generating in suggesting that the improved outcomes seen with current generation DES might mitigate the benefit of the newer, more potent P2Y12 inhibitors. However, until further evidence to the contrary emerges, the status quo will remain the status quo for dual antiplatelet therapy in ACS.

The SPYRAL HTN-OFF MED study, a randomized, blinded, sham control study of hypertensive patients off medications, demonstrated that renal denervation produced greater office and ambulatory BP reduction compared with the control group.

The SPYRAL HTN-OFF MED study may renew enthusiasm in renal denervation for the treatment of hypertension that has been absent since the results of the SYMPLICITY HTN 3 (Renal Denervation in Patients With Uncontrolled Hypertension) trial became public. Several prior reports of the safety and efficacy of renal denervation for hypertension had fostered excitement for this new therapy aimed at patients with resistant hypertension. But the patients in these studies were not blinded to their treatment allocation. In the blinded, randomized SYMPLICITY HTN 3 trial, the subjects underwent renal angiography, which served as a sham procedure for those randomized to control, and follow up evaluation was performed by blinded investigators. There was no significant difference between the two groups in the reduction in BP. And the wind went out of the sails of renal denervation.

The SPYRAL HTN-OFF MED study is the first to randomize patients with hypertension to renal denervation versus no medical therapy. Inclusion criteria required office systolic BP to be ≥150 and <180 mm Hg, or office diastolic BP ≥90 mm Hg, or ambulatory systolic BP ≥140 and <170 mm Hg. Eight enrolled subjects were blinded to their treatment group, randomized at the time of their renal angiogram (the sham procedure to maintain the blind). Urine and serum samples were analyzed to ensure that patients in both arms were not taking anti-hypertensive medications. At 3 months, there was a 5.5 mm Hg systolic and 4.8 mm Hg diastolic drop in ambulatory BP in the renal denervation group; the control group ambulatory BP dropped only 0.5 mm Hg systolic and 0.4 mm Hg diastolic, which is a statistically significant difference. Similarly, the office BP had statistically significant difference favoring renal denervation. There were no significant safety events in either arm of this study. Unlike the unipolar radiofrequency device used in the SYMPLICITY HTN 3 trial, the SPYRAL HTN-OFF MED study employed a four-pole radiofrequency, helical catheter. In another difference from the prior trial, SPYRAL HTN-OFF MED study ablations were performed in the branch vessels in addition to the main renal artery, with an average of nearly 44 ablations per subject as opposed to 11 in the SYMPLICITY HTN 3 trial. In the interim between the 2 studies, it had been demonstrated that there is a greater density of sympathetic nerves in the distal aspect of the renal arteries as opposed to the main vessel, suggesting that more distal ablations may be more effective.

The SPYRAL HTN-OFF MED study, by examining renal denervation in patients off medications, examined and confirmed the physiologic effect of renal denervation to impact the sympathetic nervous system to treat hypertension. This addressed a fundamental limitation of the SYMPLICITY HTN 3 trial, which sought to enroll subjects on maximally tolerated doses of three drugs, yet the medical regimen was not stable throughout the follow-up period. Furthermore, there was no standardized medical regimen in the SYMPLICITY HTN 3 trial. The SPYRAL HTN-OFF MED study and the SPYRAL HTN-ON MED study, which has not yet been reported, were designed as proof-of-concept studies to inform a larger pivotal trial of the helical multipolar catheter. The results of the SPYRAL HTN-OFF MED study are encouraging with respect to the potential benefit of this therapy but cannot be practice-changing yet. However, there is a significant efficacy signal that renal denervation may be a significant treatment for hypertension. We should look forward to future studies of renal denervation to confirm its role in the treatment of hypertension.

The VALIDATE-SWEDEHEART study was presented at the ESC Congress 2017 and published in the New England Journal of Medicine on August 27, 2017. This study compared 3,004 patients on bivalirudin and 3,002 patients on heparin monotherapy who were undergoing coronary revascularization for ACS, both ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI). Importantly, 90.3% of patients had radial access and were on a potent P2Y12 inhibitor, predominantly ticagrelor, used in 95% of cases. Routine use of glycoprotein IIb/IIIa inhibitors was an exclusion with bail-out use in either arm in <3% of cases.

Like the contemporary bivalirudin versus heparin trials, no advantage was seen in use of bivalirudin in patients with ACS. At 6 months, no statistically significant differences were seen in the composite incidence of death, myocardial infarction (MI), or stent thrombosis. Major bleeding, a purported advantage of bivalirudin, was no different in the 2 groups (8.6% each), and radial access was the probable reason.

In conclusion, radial access, potent P2Y12 inhibition, and heparin monotherapy are efficacious in patients with STEMI and NSTEMI; routine use of bivalirudin (an expensive drug compared with heparin) cannot be supported. Further trials are probably not warranted.

Patients with prior MI and elevated C-reactive protein (CRP) (greater than 2 mg/L) remain at unacceptably high risk (>4% annual event rate in the placebo arm of CANTOS), and this calls for additional treatments. Canakinumab 150 mg every 3 months significantly reduced the primary endpoint of cardiac death, non-fatal MI, and non-fatal stroke with a hazard ratio of 0.85 (3.86 vs. 4.50 with a difference of 0.64 per 100 person-year, p = 0.021), largely due to a reduction in MI, in patients with previous MI and residual inflammatory risk (CRP greater than 2 mg/L), and is therefore the first and only anti-inflammatory drug proven to reduce risk in patients with cardiovascular disease.

The CANTOS dataset is very robust. Although it may appear as one single trial, CANTOS is a sort of combination of 3 separate trials with a common placebo arm, including 10,061 patients for up to 5 years, representing the largest cytokine study ever done. Each of the canakinumab doses is indeed compared separately with placebo. It is therefore reassuring to see that a dose response is seen within most, if not all, endpoints, by which the 50 mg dose appears insufficient, the 150 mg dose is significantly associated with a benefit, and the 300 mg dose provides an even stronger effect for some but not all of the endpoints.

As such, CANTOS is a game-changer in the field and is likely to change practice in cardiology. This, however, may not happen rapidly or without some difficulties. For one, canakinumab is associated with a low and predictable risk of adverse events, but such events can be life-threatening. The serious adverse events occurring more frequently in canakinumab were leukopenia (0.37 vs. 0.24 per 100 person-year, difference of 0.13), serious infection (3.13 vs. 2.86 per 100 person-year, difference of 0.27), and fatal infections (0.28 vs. 0.18 per 100 person-year, difference of 0.10). Although none of these differences was statistically significant in the comparison of canakinumab 150 mg group alone versus placebo, leukopenia and fatal infection were significantly more common in the canakinumab-treated patients when the 3 groups were pooled together. Of note, the number of opportunistic infections, as defined by an ad hoc adjudication committee, was not different in canakinumab versus placebo (0.15 vs. 0.18 per 100 person-year). Chronic use of canakinumab, therefore, increases the risk of serious and lethal infections not by increasing the likelihood of opportunistic infections but rather by blunting the innate immune response to common pathogens and thus likely delaying the recognition of the clinical presentation of infection and promoting more widespread infection.

A rather unexpected clinical finding in CANTOS is the benefit of canakinumab on lung cancer incidence and cancer-related mortality. Canakinumab 150 mg was associated with a reduction in all cancer-related mortality (0.50 vs. 0.64 in placebo, absolute difference 0.14). This is likely to lead to further targeted studies.

A barrier to treating all patients with prior MI and CRP >2 mg/L with canakinumab is potential cost. In addition, treatment endpoints and duration remain unknown. These questions remain: Should patients be treated to a target CRP? Should treatment be continued long-term or intermittently?

Complete revascularization of major epicardial lesions supplying important areas of ischemic myocardium is critical.

Treating only hemodynamically significant lesions (a surrogate for ischemia-producing lesions) is associated with better outcomes while reducing the number of lesions treated.

Patients had three-vessel disease with hemodynamic confirmation of lesion severity where feasible using thin strut, bioresorbable scaffold DES with intravascular imaging for optimal lesion results and contemporary treatment of total occlusions. Patients were treated with guideline-directed medical therapy. The result was improved outcomes compared with a comparable subgroup of SYNTAX (Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery). Equivalent outcomes to the SYNTAX surgical outcomes based on pre-specified differences in major adverse cardiac event outcomes were related to lower rates of definite stent thrombosis, MI, and revascularization but not mortality.

Although this study is very enticing, a modern randomized study comparing bypass surgery will ultimately be needed for a definitive answer. These results are not surprising. Multiple studies over recent years have affirmed that for both surgery and PCI, late outcomes are better with more complete revascularization. Furthermore, the FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) and FAME II (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation 2) trials have demonstrated that "less is more" when only potentially ischemia-producing lesions are treated. This concept is supported by several trials showing that residual ischemia, more than anatomy or symptoms per se, is a better predictor of late outcome. Even in SYNTAX, PCI-treated patients with complete revascularization had comparable results to surgery with or without complete revascularization.

A last question is this: Why does complete revascularization seem less important for surgery? First, incomplete revascularization is relatively less frequent for surgical patients, at least partially, because surgical revascularization has been more readily achieved for chronically occluded arteries. In addition, surgeons are often most focused on grafting larger vessels, generally subtending the greatest amount of at risk myocardium. As a proof of principle, the Department of Veterans Affairs ROOBY (Randomized On/Off Bypass) study demonstrates that over time (at 1-year and 5-year follow-up), major adverse cardiac events and mortality outcomes are worse for less complete revascularization. This delay in observing an outcome difference by best treatment practices is an important message to interventionalists: Optimal PCI is more than "getting out of the lab!" It is achieving complete revascularization with quality lesion treatment of hemodynamically (ischemia-producing) significant lesions to achieve optimal late outcomes.

The DIVA trial was a multicenter, randomized clinical trial (RCT) that enrolled 597 veteran patients.1 At 12 months, the primary outcome (the composite of cardiac death, target vessel MI, and target vessel revascularization [TVR]) occurred in 17% of those in the DES group versus 19% in the bare-metal stent (BMS) group (p = 0.67).2 The rates for individual endpoints, including all-cause mortality, cardiac mortality, stent thrombosis, MI, target lesion revascularization, and TVR were similar between the 2 stent types.

The findings in the DIVA trial were unexpected, and they conflicted with previous observational studies and RCTs.3 However, observational studies are confounded by various types of biases and can be misleading. Nonetheless, 4 RCTs and 1 post hoc analysis of an RCT have shown that DES compared with BMS in saphenous vein graft (SVG) lesions decreased non-MI-related TVR (due to restenosis) over a 6-18-month follow-up. Also, 4 of the trials were relatively small; small trials can exaggerate therapeutic effects relative to larger trials.4 However, the largest RCT performed to date, the ISAR-CABG (Efficacy Study of Drug-eluting and Bare Metal Stents in Bypass Graft Lesions) trial, with 610 patients, also showed a significant reduction in TVR with DES compared with BMS (10% vs. 16%; p = 0·03).5 The incidence of TVR at 12 months in the DIVA trial compared with the ISAR-CABG trial was lower in the BMS group (11% vs. 15.5%), which could have resulted from improvements in BMS technology over time. However, in the DES group in the DIVA trial, new-generation stents were used 89% of the time, and the TVR rate was high compared with the ISAR-CABG trial (12% vs. 9.6%).

One potential limitation of the DIVA trial is its termination before its revised enrollment target was reached. Another is the average age of SVGs in the DES group, which was greater than it was in the BMS group (13.8 ± 6.7 years vs. 12.8 ± 6.8 years; p = 0.026), potentially creating a bias favoring the BMS group. Furthermore, routine follow-up angiographies were not allowed in the DIVA trial, but two thirds of the patients underwent routine follow-up angiographies (part of the study protocol) in the ISAR-CABG trial. So, the benefits on TVR with DES could have been driven by angiographic re-stenotic (clinically silent) lesions in the ISAR-CABG trial.

In conclusion, the findings of the DIVA trial raised more questions, calling for additional studies about the best stent strategy to use for SVG intervention.